1. Field of the Invention
The present invention relates to processes for the synthesis of thieno[3,2-c]pyridine derivatives, particularly ticlopidine, and specifically to an improved process for conversion of suitably functionalized derivatives of 2-(2'-thienyl)ethanol to 2-(2'-thienyl)ethylamine.
2. Background Information
Ticlopidine is a compound with desirable blood platelet aggregation inhibition qualities. Previous technology for the preparation of ticlopidine has entailed a low yielding, labor intensive process, employing certain potentially hazardous and expensive materials. The cost of preparing ticlopidine has, therefore, been high. It has been desired to provide improved synthetic process technology that allows for a higher conversion, reduced labor usage, and the elimination of costly, potentially dangerous materials.
A variety of synthetic approaches to making ticlopidine have been described in the art, including improvements on the various steps of such synthetic processes, e.g., as described below.
Ticlopidine was first described by Castaigne in U.S. Pat. No. 4,051,141, where the synthesis thereof was accomplished by condensation of a thieno[3,2-c]pyridine with o-chlorobenzyl chloride.
One desirable method of preparing ticlopidine calls for 2-(2'-thienyl)ethylamine as a key intermediate. The method involved preparation of a 2-(2'-thienyl)ethanol, conversion to the corresponding sulfonate derivative and then to the amine, followed by cyclization and benzylation with o-chlorobenzyl-chloride to give ticlopidine free base, as described by Braye in U.S. Pat. No. 4,127,580.
Previous methods for the preparation of 2-(2'-thienyl)ethylamine have suffered from several disadvantages, including low yields (e.g., where the reactions resulted in mixtures of undesirable side products) and high cost.
For example, Braye, U.S. Pat. No. 4,128,561 describes a two-step process of making 2-(2'-thienyl)ethylamine by converting 2-(2'-thienyl)ethanol to N-2-(2'-thienyl)ethyl phthalimide, and then treating the phthalimide with diethylenetriamine to form the amine. Braye also describes the amination of 2-(2'-thienyl)alkyl sulfonates with ammonia at elevated temperature and pressure. Braye discloses problems encountered in the preparation of primary amines with ammonia, i.e., the tendency for the process to form secondary and tertiary amines as side products.
A process where 2-(2'-thienyl)ethylbromide is treated with alcoholic ammonia at ordinary temperature for 8 days to produce 2-(2'-thienyl)ethylamine is described by Blicke, et al., J. Am. Chem. Soc., 64, 3, 477-480 (1942).
Generally, the synthesis of primary amines with ammonia has been found to be disadvantageous because primary amines are more basic than ammonia; this will cause the primary amine to preferentially attack the reaction substrate over the ammonia, resulting in the formation of secondary and tertiary amines. Advanced Organic Chemistry, March, J., 2nd Ed., 376, (1977). Such formation of undesired secondary and tertiary amines, of course, reduces the yield of the desired primary amine and creates the need for additional purification and isolation steps, which further decrease the yield and increase the cost of the desired primary amine. The formation of undesired secondary and tertiary amines has remained a problem until the present invention.
Other synthetic approaches to making 2-(2'-thienyl)ethylamine have been disclosed in the art, for example, as described below.
The reduction of 2-(2'-thienyl)acetamide with a hydride, e.g., lithium aluminum hydride to form 2-(2'-thienyl)ethylamine is described in Japanese Kokai J6 1221-184-A.
The electrochemical reduction of 2-nitro-2-vinyl thiophene to 2-amino-2-ethyl-thiophene is described in UK Patent Application GB 2,013,196A.
The catalytic hydrogenation of thienyl acetonitrile to form thienyl ethylamines is described in European Patent No. 274,324.
The reduction of nitrovinyl thiophenes with a hydride, e.g., lithium aluminum hydride to form thiophene ethylamines is described in J. Heterocyclic Chem., 7, 1257-1268 (1970).
The reduction of arylacetonitriles with lithium aluminum hydride/aluminum chloride to form the corresponding 2-aryl-1-aminoethanes is described in Synthesis, 1, 40-42, (1987).